Program Director/Principal Investigator (Last, First, Middle): PROJECT SUMMARY / ABSTRACT Bicuspid aortic valve (BAV) is the most frequent congenital valvular cardiac malformation, occurring in 0.5- 1.2% of the US population. Over 20% of patients with BAV develop thoracic aortic aneurysm or dissection (TAAD) requiring surgery. Yet, untreated TAAD is associated with high morbidity and mortality rates dying of aortic rupture, cardiac tamponade, acute aortic insufficiency and organ ischemia. TAAD is relatively rare in the general population, but is more frequent in individuals with BAV, often requiring surgery at a much younger age than the general population. Yet, we know little of the genetic etiology, cellular biology and modifiers of disease progression for BAV to TAAD, including heterogeneity of BAV leaflet fusion morphology that has impact upon blood flow patterns in the aortic root and ascending aorta. Common variants in the fibrillin-1 (FBN1) gene in non-familial aortic aneurysm in patients have been observed in patients with and without BAV. Using genome-wide association, we have observed modest signals from common non-coding variants in FBN1 and other genes, with aortic dimensions in BAV patients. The etiology and presentation of TAAD is most likely due to a full spectrum of frequent to private mutations that can only be fully explored with GWAS of a sufficiently-powered cohort of well-phenotyped patients. These mutations may have overlap with TAAD-associated mutations in patients with a tricuspid aortic valve. In order to expeditiously advance the field of BAV TAAD research, with adequate sample size for genetic studies that include a wide range of BAV phenotypes, we plan to use the pre-exisiting DNA, epidemiologic and well-imaged phenotypes of patients with BAV, from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) housed in BioLINCC. To increase power of the study, we will use additional BAV patients, along with comparable control patients from other cohorts including the BAV Consortium (BAVCon), the Michigan Cardiovascular Health Improvement Project (CHIP) and BAV Registry, and the University of Texas, Houston. This proposal provides a credible and best mechanism for identifying rare, as well as common genetic variation causing TAAD in individuals with BAV, notably by inclusion of the GenTAC resources housed at BIOLINCC, in concert with the extensive resources of other supplemental studies. We believe these methods will allow for critical advances in BAV research and potentially, patient management. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page